Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes and lymphocytes. They can be released by many kinds of tissue cells after activation. Continuous release of chemokines at sites of inflammation mediates the ongoing migration of effector cells in chronic inflammation (Baggiolini, et. al., Nature 15:365 (1994)). Indeed, chemokines have been implicated in a wide range of human acute and chronic inflammatory diseases including, but not limited to, respiratory diseases such as asthma, inflammatory bowel disease, allergic disorders and certain autoimmune diseases such as rheumatoid arthritis.
Chemokines exert their biological activity by binding to specific G-protein receptors, which then transduce signals important for the development and trafficking of specific leukocyte subsets (Baggiolini, et. al., Nature 15:365 (1994)). A number or chemokine receptors have been characterized and each are differentially expresssed among leukocyte populations. Significantly, each chemokine binds specifically to a single receptor or to a small group of receptors. Thus, the recruitment and activation of specific classes of leukocytes or lymphocytes can be modulated by agents which selectively act at one chemokine receptor and/or block the activity of a specific chemokine. Agents which selectively block the activity of a specific chemokine or chemokine receptor are therefore useful in treating inflammatory diseases caused by aberrant activation of leukocytes or lymphocytes which express those chemokine receptors (or are activated by the chemokine) and minimally affect immune system cells which express other chemokine receptors.
CCR8 is a chemokine receptor (see WO 99/065561) whose expression is primarily restricted to Th2 cells (Zingoni et al., J. Immunol. 161:547 (1998) and D'Ambrosio et al., J. Immunol. 161:5111 (1998)). I-309 is a ligand for CCR8 and has shown to be chemotactic for Th2 cells in vitro (D'Ambrosio et al., J. Immunol. 161.5111 (1998). CCR8 is also involved in eosinophil recruitment (see WO 99/065561). Thus, antagonists for CCR8 are expected to be useful in treating disorders mediated by Th2 and eosinophil cells, e.g., asthma.